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2719 A Randomized, Phase II Study with Biomarker Analysis of Panobinostat with or without Rituximab in Relapsed Diffuse Large B Cell Lymphoma

Lymphoma: Chemotherapy, excluding Pre-Clinical Models
Program: Oral and Poster Abstracts
Session: 623. Lymphoma: Chemotherapy, excluding Pre-Clinical Models: Poster II
Sunday, December 6, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Sarit Assouline1*, Michael Crump, MD2, Torsten Holm Nielsen1*, Miguel Alcaide, B. Sc., Ph. D.3*, David Macdonald, MD, FRCPC4, Axel Tosikyan5, Tina Haliotis1*, Celia Greenwood1*, Kathleen Klein Oros6*, Ryan Morin, PhD3*, Nathalie Johnson, MD, PhD7 and Koren Kathleen Mann, PhD1

1McGill University, Montreal, QC, Canada
2Princess Margaret Hospital, Toronto, ON, Canada
3Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada
4QEII Health Sciences Centre, Halifax, NS, Canada
5Hopital du Sacre-Coeur de Montreal, Montreal, QC, Canada
6McGIll University, Montreal, QC, Canada
7Hematology, Jewish General Hospital, McGill University, Montreal, QC, Canada

INTRODUCTION: Novel therapies which consider the molecular diversity of diffuse large B cell lymphoma (DLBCL) are needed to salvage patients who fail to respond to standard chemoimmunotherapy. The majority of DLBCL contain mutations in histone modifying enzymes (HME) which suggests that histone deacetylase inhibitors (HDI) should be active. Preclinical data suggest that they also augment the effect of rituximab.

METHODS: In this randomized phase II study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI, 30 mg orally 3 times a week, with or without rituximab, in 40 patients with relapsed and refractory DLBCL (median 3 prior regimens, range1-9). Tumors were sequenced for mutations known to be associated with DLBCL, and serial biopsies were analyzed for changes in biomarkers.

RESULTS: 21 patients were treated with panobinostat alone and 19 with panobinostat and rituximab. Overall, 12/40 patients (30%) responded to panobinostat (95% confidence interval 16.6%-46.5%) the addition of rituximab did not increase responses. The median duration of response was 14.5 months (95% confidence interval 9.4 to not reached) (Figure). At a median follow up of 17.5 months for responders, 6 of 12 patients have not progressed. Patients with dual expression of MYC and BCL2 (6/27) and those with FAS mutations (5/33) did not respond although responses were seen in 5/10 patients with TP53 mutations. Responses were seen in 8/24 patients with mutations in HME genes. Patients with MEF2B mutations had the greatest odds of response (P<0.05) and a higher number of HME mutations tended to increase the odds of response. Changes in histone H3 acetylation and MYC expression were observed but did not correlate with response.

CONCLUSION: Panobinostat induces durable responses in some patients with relapsed DLBCL, and accompanying biomarker analyses identified DLBCL subgroups likely to respond.

Figure: Progression free survival overall and for responders, N=40 patients.

Disclosures: Assouline: Novartis: Consultancy , Honoraria , Research Funding ; Roche: Consultancy , Honoraria , Research Funding ; Janssen: Honoraria ; Celgene: Consultancy . Off Label Use: panobinostat for the treatment of diffuse large B cell lymhpoma. Crump: Seattle Genetics: Consultancy ; Celgene: Consultancy ; Roche Canada: Consultancy . Tosikyan: Novartis: Consultancy .

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